Physiological factors which influence the initiation and cessation of cortical epileptic discharge are important in understanding the pathophysiology of this process. Extracellular ion concentrations in the brain influence neuronal behavior and could serve as modulators of epileptic discharge; in fact, this has been shown to be the case for extracellular [K+]. Extracellular pH (pH/o) has recently been shown to directly influence neuronal excitability and to modulate the action of excitatory neurotransmitters at the N-methyl D-Aspartate receptor. Furthermore, large and long-lasting changes in pH/o occur with intense neural activity. Activity-dependent pH/o shifts in the acid direction appear to be mediated, at least in part, by glial cells. These observations prompt the hypothesis that epileptic discharge is influenced by pH/o and that activity-dependent extracellular acidification, mediated in part by glial cells, acts as a negative feedback mechanism to inhibit epileptic discharge. These hypotheses will be tested using neocortical and hippocampal brain slices and ion-sensitive microelectrodes. The role of glial cells in mediating extracellular acidification will be studied using ion sensitive microelectrodes and the 'pure glial' rat optic nerve. Aspects of intracellular pH regulation that might contribute to extracellular acidification will be analyzed in cultured glial cells using microfluorometry. These studies will provide useful new information about the mechanisms of pH/o fluctuations in the brain while assessing the importance of pH/o as a modulator of the excessive neural activity seen in epilepsy.